The AIDS wasting syndrome (AWS) is a devastating complication of late- stage HIV disease, characterized by a profound loss of lean body mass, relative fat sparing and altered substrate metabolism. Recent evidence suggests that hypogonadism and abnormalities in endogenous growth hormone (GH) secretion are common in patients with the AWS. In a preliminary study, we have shown that hypogonadism is present in 49% of men with advanced HIV infection. Prior studies in non HIV-infected populations demonstrate that deficiencies of the potent anabolic hormones testosterone or GH result in decreased lean body mass, fat sparing and alterations in substrate metabolism nearly identical to those seen in the AWS. Furthermore, preliminary data suggest that short-term administration of GH to patients with the AWS increases weight and protein synthesis. However, these studies have been limited to men and have not investigated the combined anabolic effects of testosterone and GH in hypogonadal men with the AWS or the anabolic effects of GH in women with the AWS. In addition, no previous study has examined the important interaction between gonadal function, endogenous GH secretion and the anabolic effects of exogenously administered GH in women with the AWS. This study will simultaneously test three novel hypotheses: l) androgen deficiency contributes to the pathogenesis of the AWS and testosterone replacement will build lean body mass in hypogonadal men with the AWS, 2) testosterone therapy will have a combined anabolic effect with GH and 3) GH will have a sustained anabolic effect in women with the AWS, determined, in part, by gonadal function. To answer these questions, we have designed a 12 month randomized, placebo controlled, double-blind factorial study of testosterone and GH in 60 hypogonadal and 30 eugonadal men with the AWS. Forty women will be enrolled in the protocol to determine whether gender-based differences in body composition and gonadal function affect the sustained anabolic responses to GH in women with the AWS. The primary endpoints chosen for this study are weight and lean body mass. Previous studies have used indirect measures of lean body mass subject to changes in hydration status. For this reason we will use a state of the art technique, K4O isotope analysis, to directly determine lean body mass. In addition, we will determine changes in fat, muscle and total body water, along with nutritional variables, energy expenditure and nitrogen balance to accurately assess body composition and substrate metabolism in response to testosterone and GH. We will characterize gonadal function in both men and women using measurements of gonadal steroid levels, gonadotropin reserve and ovulatory status. Growth hormone secretory dynamics will be assessed by GH pulse analysis, provocative testing and integrated markers of GH secretion, including insulin-like growth factor-I (IGF-I) and its binding proteins. Our proposed studies will contribute significantly to an understanding of the pathogenesis of the AWS and may elucidate novel treatment strategies for both men and women with the AWS.